Dent's disease, is a disorder that is characterized by low molecular weight proteinuria, aminoaciduria,[unreadable] glycosuria, polyuria, hyperphosphaturia (Fanconi syndrome) as well as hypercalciuria, nephrocalcinosis,[unreadable] nephrolithiasis. Dent's disease has been established to be caused by mutations of the CICN-5 gene, the[unreadable] product of which is CIC-5 a voltage-gated chloride channel expressed in highest abundance in renal tubules[unreadable] of the proximal nephron. Our preliminary studies in a CICN-5 knockout mouse model, shows that it[unreadable] recapitulates the features of Dent's disease including hypercalciuria, aminoaciduria, glycosuria, low[unreadable] molecular weight proteinuria, renal calcifications, and renal failure. THE PRPOSED STUDY WILL HELP[unreadable] DEFINE THE UNDERLYING MOLECULAR BASIS OF THESE REABSORPTION DEFECTS.[unreadable] Specific aim 1: How do other CIC channels or CIC-5 exchange regulate apical endocytosis in proximal[unreadable] tubule cells? 1 A. Do CIC-3 and/or CIC-4 contribute to the residual acidification and apical endocytosis in the[unreadable] ko cells? 18. Does the over-expression of CIC-3 and CIC-4 restore albumin uptake in CIC-5 ko cells? Does[unreadable] the chloride/proton exchanger activity of CIC-5 in ko cells restore normal albumin uptake? Specific Aim 2:[unreadable] What is the relationship between loss of CIC-5 and the downregulation of megalin in the ko proximal tubule[unreadable] cells? 2A. Is the half-life of megalin shorter in ko versus wt cells? 2B. How is the recycling behavior of[unreadable] megalin altered in ko versus wt cells? 2C. Does endosomal pH, or lack of CIC-5, regulate megalin[unreadable] dynamics? Specific Aim 3. How does the loss of CIC-5 lead to changes in the distribution/activity of NHE3[unreadable] and other apical transporters? 3A. Is NHE3 activity decreased in the proximal tubule, ileum or jejunum of ko[unreadable] mice? 3B. What are the steady state levels and dynamics of NHE3 in ko proximal tubules cells? 3C. What[unreadable] are the steady state levels and dynamics of NaPi-lla in ko proximal tubule cells? 3D, Does endosomal pH, or[unreadable] lack of CIC-5, regulate NHE3 or NaPi-lla dynamics?[unreadable] The long term goal of this research is to understand how molecular events cause the phenotypical[unreadable] outcomes of Dent's disease.